Paige B. Clark

Predictive value of 18-fluoro-deoxy-glucose-positron emission tomography (18F-FDG-PET) in the identification of responders to chemoradiation therapy for the treatment of locally advanced esophageal cancer.

Objective:To evaluate the utility of 18F-FDG-PET in predicting response to concomitant chemoradiation in locally-advanced esophageal cancer. Summary Background Data:Approximately 25% of esophageal cancer patients experience a pathologic complete response (pCR) to preoperative chemoradiation therapy. Computed tomography, endoscopy, and endoscopic ultrasound are unable to identify patients experiencing a pCR. Growing evidence supports the use of 18F-FDG-PET in the staging of esophageal cancer in its ability to detect occult metastatic and lymph nodal disease. The identification of patients with a pCR to chemoradiation could potentially spare those patients the morbidity associated with a resection. Methods:Eligibility criteria included T3-T4N0M0 or T1-T4N1M0 esophageal cancer. Patients underwent an initial 18F-FDG-PET before treatment and then repeated 4 to 6 weeks after chemoradiation, prior to the esophagectomy. Chemoradiation consisted of: cisplatinum, 5-fluorouracil, and radiation to a median dose of 50.4 Gy. Pathologic response was determined from a systematic review of the esophagectomy specimens. Results:Sixty-four patients have completed therapy to date. Response was as follows: pCR 27%, pathologic residual microscopic (pCRmicro) 14.5%, partial response 19%, and stable or progressive disease 39.5%. A pretreatment standardized uptake value (SUVmax1hour) ≥15 was associated with an observed 77.8% significant response (pCR + pCRmicro) compared with 24.2% for patients with a pretreatment SUVmax1hour <15 (P = 0.005). Significant response was observed in 71.4% of patients with a decrease in SUVmax1hour ≥10 compared with 33.3% when the SUVmax1hour decreased <10 (P = 0.004). Conclusions:Pretreatment and posttreatment 18F-FDG-PET can be useful for predicting significant response to chemoradiation in esophageal cancer. These data should be considered in evaluation of patients for esophagectomy after chemoradiation.

Outcomes of Patients With Esophageal Cancer Staged With [18F]Fluorodeoxyglucose Positron Emission Tomography (FDG-PET): Can Postchemoradiotherapy FDG-PET Predict the Utility of Resection?

PURPOSE To determine whether [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) can delineate patients with esophageal cancer who may not benefit from esophagectomy after chemoradiotherapy. PATIENTS AND METHODS We reviewed records of 163 patients with histologically confirmed stage I to IVA esophageal cancer receiving chemoradiotherapy with or without resection with curative intent. All patients received surgical evaluation. Initial and postchemoradiotherapy FDG-PET scans and prognostic/treatment variables were analyzed. FDG-PET complete response (PET-CR) after chemoradiotherapy was defined as standardized uptake value ≤ 3. RESULTS Eighty-eight patients received trimodality therapy and 75 received chemoradiotherapy. Surgery was deferred primarily due to medical inoperability or unresectable/metastatic disease after chemoradiotherapy. A total of 105 patients were evaluable for postchemoradiotherapy FDG-PET response. Thirty-one percent achieved a PET-CR. PET-CR predicted for improved outcomes for chemoradiotherapy (2-year overall survival, 71% v 11%, P < .01; 2-year freedom from local failure [LFF], 75% v 28%, P < .01), but not trimodality therapy. On multivariate analysis of patients treated with chemoradiotherapy, PET-CR is the strongest independent prognostic variable (survival hazard ratio [HR], 9.82, P < .01; LFF HR, 14.13, P < .01). PET-CR predicted for improved outcomes regardless of histology, although patients with adenocarcinoma achieved a PET-CR less often. CONCLUSION Patients treated with trimodality therapy found no benefit with PET-CR, likely because FDG-PET residual disease was resected. Definitive chemoradiotherapy patients achieving PET-CR had excellent outcomes equivalent to trimodality therapy despite poorer baseline characteristics. Patients who achieve a PET-CR may not benefit from added resection given their excellent outcomes without resection. These results should be validated in a prospective trial of FDG-PET-directed therapy for esophageal cancer.

Reversal of hypermetabolic brown adipose tissuein F-18 FDG PET imaging

Objectives: With the increasing application of F-18-fluorodeoxyglucose (FDG) positron emission imaging, there has been an evolving appreciation for the range of normal variants and the realization that false-positives can lead to serious consequences. Results: One of the most common causes of a false-positive study is the uptake of FDG in areas of hypermetabolic brown adipose tissue (HBAT). Areas of involvement are often spatially closely related to important lymph node groups in the neck, axilla, and upper mediastinum, making critical differentiation difficult, even with PET-CT. Conclusions: FDG uptake in HBAT has been noted to occur more frequently in cold months and benzodiazepines have been proposed for its prevention. The use of these drugs is, in our experience, of limited value and may complicate patient care in both inpatient and outpatient populations. In this report, we describe considerable success by completely reversing HBAT in 9 of 10 sequential patients with simple core warming maneuvers, which obviate the use of benzodiazepines.

Prediction of Cardiac Events in Patients With Reduced Left Ventricular Ejection Fraction With Dobutamine Cardiovascular Magnetic Resonance Assessment of Wall Motion Score Index

OBJECTIVES The purpose of this study was to assess the utility of dobutamine cardiovascular magnetic resonance (DCMR) results for predicting cardiac events in individuals with reduced left ventricular ejection fraction (LVEF). BACKGROUND It is unknown whether DCMR results identify a poor cardiac prognosis when the resting LVEF is moderately to severely reduced. METHODS Two hundred consecutive patients ages 30 to 88 (average 64) years with an LVEF <or=55% that were poorly suited for stress echocardiography underwent DCMR in which left ventricular wall motion score index (WMSI), defined as the average wall motion of the number of segments scored, was assessed at rest, during low-dose, and after peak intravenous infusion of dobutamine/atropine. All participants were followed for an average of 5 years after DCMR to ascertain the post-testing occurrence of cardiac death, myocardial infarction (MI), and unstable angina or congestive heart failure warranting hospital stay. RESULTS After accounting for risk factors associated with coronary arteriosclerosis and MI, a stress-induced increase in WMSI during DCMR was associated with future cardiac events (p < 0.001). A DCMR stress-induced change in WMSI added significantly to predicting future cardiac events (p = 0.003), after accounting for resting LVEF, but this predictive value was confined primarily to those with an LVEF >40%. CONCLUSIONS In individuals with mild to moderate reductions in LVEF (40% to 55%), dobutamine-induced increases in WMSI forecast MI and cardiac death to a greater extent than an assessment of resting LVEF. In those with an LVEF <40%, a dobutamine-induced increase in WMSI does not predict MI and cardiac death beyond the assessment of resting LVEF.

Is parathyroid carcinoma indeed a lethal disease

BackgroundParathyroid carcinoma is a rare malignancy with a wide range of aggressiveness. There is no current staging system. Our primary aim was to review the presentation, diagnosis, surgical treatment, and outcomes of patients, with the goal of assessing the incidence of death related to parathyroid carcinoma.MethodsThe authors present a retrospective chart review on patients with parathyroid carcinoma from 1975 to 2004, identified by the tumor registry of a single tertiary-care center. Diagnoses were confirmed histologically, clinical and radiographical data were recorded, and statistical analyses were performed.ResultsTwenty-three cases were identified. The mean patient age was 54 years. The female:male ratio was 1.5:1. Follow-up ranged from 1 month to 23 years (median, 134 months). Mean preoperative calcium was 12.9 mg/dL. Median parathyroid hormone was 290 pg/mL. Two patients (9%) had an asymptomatic presentation, and five (22%) presented with a palpable neck mass. Only nine (39%) underwent initial comprehensive en-bloc resection. Median survival was 22 years. Five- and 10-year survival was 85.9% and 69.4%, respectively. Five- and 10-year survival with en-bloc resection was 90% and 67.5%, respectively. Local resection resulted in survival rates of 82.5% and 70.7%. Three of ten deaths were attributed to parathyroid carcinoma. In recurrent disease, computed tomography and scintigraphy had localization rates of 53% and 67%, respectively, with a concordance of 22%.ConclusionsLong-term survival is possible with parathyroid carcinoma. Death associated with parathyroid carcinoma was uncommon. A staging may be warranted despite the rarity of this disease.

Ongoing β-Cell Turnover in Adult Nonhuman Primates Is Not Adaptively Increased in Streptozotocin-Induced Diabetes

OBJECTIVE β-Cell turnover and its potential to permit β-cell regeneration in adult primates are unknown. Our aims were 1) to measure β-cell turnover in adult nonhuman primates; 2) to establish the relative contribution of β-cell replication and formation of new β-cells from other precursors (defined thus as β-cell neogenesis); and 3) to establish whether there is an adaptive increase in β-cell formation (attempted regeneration) in streptozotocin (STZ)-induced diabetes in adult nonhuman primates. RESEARCH DESIGN AND METHODS Adult (aged 7 years) vervet monkeys were administered STZ (45–55 mg/kg, n = 7) or saline (n = 9). Pancreas was obtained from each animal twice, first by open surgical biopsy and then by euthanasia. β-Cell turnover was evaluated by applying a mathematic model to measured replication and apoptosis rates. RESULTS β-Cell turnover is present in adult nonhuman primates (3.3 ± 0.9 mg/month), mostly (∼80%) derived from β-cell neogenesis. β-Cell formation was minimal in STZ-induced diabetes. Despite marked hyperglycemia, β-cell apoptosis was not increased in monkeys administered STZ. CONCLUSIONS There is ongoing β-cell turnover in adult nonhuman primates that cannot be accounted for by β-cell replication. There is no evidence of β-cell regeneration in monkeys administered STZ. Hyperglycemia does not induce β-cell apoptosis in nonhuman primates in vivo.

Providing optimal preoperative localization for recurrent parathyroid carcinoma: A combined parathyroid scintigraphy and computed tomography approach

Purpose: The incidence of parathyroid carcinoma is approximately 0.5% to 5% in patients with primary hyperparathyroidism. Recurrent parathyroid carcinoma is treated with surgical resection of all sites of disease to ameliorate systemic manifestations of hyperparathyroidism, primarily hypercalcemia. This study investigates the role of parathyroid scintigraphy and computed tomography (CT) imaging in recurrent parathyroid carcinoma. Materials and Methods: A retrospective chart review was performed on 8 patients diagnosed with recurrent parathyroid carcinoma at our tertiary care institution between 1975 and 2001. Surgical reports, histopathology, parathyroid scintigraphy, and CT findings were recorded. Surgical reports and radiologic studies were compared for concordance of recurrence sites. Results: There were 32 imaging studies before reoperation: 15 parathyroid scintigraphy and 17 CTs. Of 15 sites of recurrence potentially seen on scintigraphy, 10 were true-positive (67%). Of 17 sites of recurrence potentially seen on CT, 9 were true-positive (53%). Of the 8 false-negatives on CT, 7 of these recurrences were in the surgical bed (88%). There were 9 instances in which CT and scintigraphy were performed preoperatively for comparison and correlation. CT and scintigraphic findings were incongruent in 7 of 9 of these cases (78%). Conclusion: Successful surgical intervention for recurrent parathyroid carcinoma requires accurate preoperative localization studies and complete excision of metastases. Our data supports combined analysis of parathyroid scintigraphy and CT for patients with recurrent disease before reoperation. Additionally, our review suggests that sensitivity may be optimized with SPECT parathyroid scintigraphy and close correlation with CT.

Left ventricular infarct size assessed with 0.1 mmol/kg of gadobenate dimeglumine correlates with that assessed with 0.2 mmol/kg of gadopentetate dimeglumine.

Objective: To determine myocardial infarct (MI) size during cardiovascular magnetic resonance at 1.5 Tesla using 0.1 mmol/kg body weight of gadobenate dimeglumine (Gd-BOPTA) and 0.2 mmol/kg body weight of gadopentetate dimeglumine (Gd-DTPA). Methods: Twenty participants (16 men, 4 women), aged 58 ± 12 years, with a prior chronic MI were imaged in a crossover design. Participants received 0.2 mmol/kg body weight of Gd-DTPA and 0.1 mmol/kg body weight of Gd-BOPTA on 2 occasions separated by 3 to 7 days. Results: The correlations were high between Gd-DTPA and Gd-BOPTA measures of infarct volume (r = 0.93) and the percentage of infarct relative to left ventricular myocardial volume (r = 0.85). The size and location of the infarcts were similar (P = 0.9) for the 2 contrast agents. Interobserver correlation of infarct volume (r = 0.91) was high. Conclusions: In chronic MI, late gadolinium enhancement identified with a single 0.1 mmol/kg body weight dose of Gd-BOPTA is associated in volume and location to a double (0.2 mmol/kg body weight) dose of Gd-DTPA. Lower doses of higher relaxivity contrast agents should be considered for determining left ventricular myocardial infarct size.

Enhanced Scintigraphic Protocol Required for Optimal Preoperative Localization Before Targeted Minimally Invasive Parathyroidectomy

At our tertiary care institution, a targeted minimally invasive parathyroidectomy (MIP) is the preferred surgical procedure for primary hyperparathyroidism. Similar to unilateral neck exploration (UNE), preoperative scintigraphic localization of the adenoma in relation to the midline is required. However, in contrast to the abbreviated standard incision for UNE, 2 distinct incision sites, 1 medial and 1 lateral, are available on each side with MIP. The incision site is ultimately chosen based on scintigraphic determination of the adenomas vascular origin to facilitate ligation and removal. Unfortunately, the scintigraphic location of a parathyroid adenoma does not necessarily reflect the site of its vascular origin. We reviewed our database to identify factors that accurately predict the site of vascular origin of parathyroid adenomas. A retrospective chart review was performed on 125 patients who underwent Tc-99m sestamibi scintigraphy and parathyroidectomy. Scintigraphic localization, surgical findings, and histopathology were recorded. Preoperative image interpretations that were discordant with operative findings were independently reviewed. Scintigraphy identified the presence of an adenoma in 105 of 118 patients (89%) with primary hyperparathyroidism. In 17 of the 105 cases (16%), the scintigraphic interpretation did not accurately reflect the site of superior or inferior vascular origin seen at surgery. In many discordant cases, anterior images were insufficient for determining the vascular origin. The posterior displacement of an adenoma in relation to the thyroid on early lateral images was often critical in determining the superior or inferior vascular origin. Scintigraphic determination of the superior or inferior vascular origin of a parathyroid adenoma directs incision placement for MIP. Imaging protocols should include early lateral images when localizing parathyroid adenomas before minimally invasive parathyroidectomy.

Dual Radiotracer Analysis of Cholinergic Neuronal Changes in Prediabetic Mouse Pancreas

BACKGROUND Pancreatic neuronal changes associated with beta cell loss in type 1 diabetes mellitus are complex, involving, in part, parasympathetic mechanisms to compensate for preclinical hyperglycemia. The parasympathetic neurotransmitter acetylcholine (ACh) mediates insulin release via M3 muscarinic receptors on islet beta cells. The vesicular ACh transporter (VAChT) receptor has been shown to be a useful marker of cholinergic activity in vivo. The positron emission tomography (PET) radiotracer (+)-4-[(18)F]fluorobenzyltrozamicol ([(18)F]FBT) binds to the VAChT receptor on presynaptic cholinergic neurons and can be quantified by PET. The compound 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), available in a tritiated form, binds to M3 muscarinic receptors on beta cells and is a potential target for assessing pancreatic beta cell mass. In this study, we investigate the feasibility of dual radiotracer analysis in identifying neurofunctional changes that may signify type 1 diabetes mellitus in its early preclinical state. METHODS Ex vivo determinations of pancreatic uptake were performed in prediabetic nonobese diabetic mice and controls after intravenous injection of [(18)F]FBT or 4-[(3)H]DAMP. Beta cell loss in prediabetic mice was confirmed using immunohistochemical methods. RESULTS [(18)F]FBT uptake was significantly higher in prediabetic pancreata than controls: 3.22 +/- 0.81 and 2.51 +/- 1.04, respectively (P < 0.03). 4-[(3)H]DAMP uptake was significantly lower in prediabetic pancreata than controls: 0.612 +/- 0.161 and 0.968 +/- 0.364, respectively (P = 0.01). CONCLUSIONS These data suggest that a combination of radiotracer imaging agents that bind to neuronal elements intimately involved in insulin production may be an effective method of evaluating changes associated with early beta cell loss using PET.